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YEONJI JANG, Sang-Mok Lee, Hyoung Oh Jun, Jin Hyoung Kim, Jeong Hun Kim, Byung Joo Lee; Rapamycin ameliorates ethambutol induced toxic optic neuropathy by facilitating mitophagy. Invest. Ophthalmol. Vis. Sci. 2016;57(12):5067.
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© ARVO (1962-2015); The Authors (2016-present)
Ethambutol (EMB) is the most common causative agent of toxic optic neuropathy, the pathogenesis of which is still obscure. In this study, we aimed to determine the exact mechanism of neuronal death in EMB induced toxic optic neuropathy (EON) and the address the role of autophagy in EON.
LC3 conversion and activation of apoptotic cascade according to EMB treatment were evaluated in Y79, human retinoblastoma cell. Viability of EMB treated Y79 cell was checked with and without rapamycin (RM). Temporal change of mitochondrial membrane potential (ΔΨm) was determined using JC-1 probe after EMB±RM treatment. The effect of EMB on the phosphorylation and mitochondrial translocation of parkin was evaluated. C57BL/6 mice were injected with EMB (intraperitoneal injection, 200 mg/kg/day) for 6 weeks. Retinal LC3 conversion and apoptotic cell death was determined with western blot and TUNEL assay, respectively. The protected effect of intravitreal rapamycin injection on retinal ganglion cell loss was evaluated by retrograde labeling technique.
EMB treatment induced depolarization of ΔΨm, LC3 conversion and cleavage of caspase 3 in Y79 cell. Rapamycin pre-treatment prevented EMB induced depolarization of ΔΨm and rescued Y79 from EMB induced cell death. Phosphorylation and mitochondrial translocation of parkin were detected after EMB treatment and in vitro knockdown of PARK2 elevated the susceptibility of Y79 cell to EMB induced cell death. In the retinal tissue of EON mouse model, EMB induced LC3 conversion and apoptosis of retinal ganglion cell. This selective loss of retinal ganglion cell was significantly alleviated by RM co-treatment.
EMB induces depolarization of ΔΨm and subsequent apoptotic cell death of retinal neuronal cell. RM facilitates mitophagy in retinal neuron, thus protect it from EMB induced apoptosis.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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